Use of (+)-1-[(3,4,5-trimethoxy)-benzyloxymethyl]-1-phenyl-N,N-dimethyl-n-propylamine to increase gastric discharge in a subject

ABSTRACT

(+)-1-[(3,4,5-trimethoxy)-benzyloxymethyl]-1-phenyl-N,N-dimethyl-n-pro pylamine of formula  &lt;IMAGE&gt;  is a medicament of use in gastroenterology.

This is a continuation of application Ser. No. 07/367,603, filed Jun.19, 1989, now abandoned.

The object of the present invention is a medicament which, whenadministered orally, increases the gastric discharge, on the one hand,and, on the other, is antispasmodic thus having an influence on variousdisorders of the gastrointestinal tract.

It is known that gastric discharge may be increased or accelerated byvarious compounds. So, metoclopramide which since 1964 has beensuggested as an antiemetic and modifier of digestive behavior possessesthis property. However, this product which belongs to the group ofneuroleptic drugs requires delicate use, as indicated by thecontra-indications, precautions for use, medicinal interactions andundesired effects cited in the "Dictionnaire Vidal"- Ed. 1988 p. 1320.

Therefore, the restrictions indicated for its use in combination withanticholinergic derivatives, antiparkinsonian compounds and neurolepticdrugs, with which activity inhibitions as well as possible centrallyacting synergies are reported, limit in particular its indication.

M. Gue et al. (Gastroenterol. Clin. and Biol., 1988, 12, 2) haverecently shown that two compounds hitherto known for their analgesicproperty cause an increased gastric discharge in the dog, whenadministered orally. The authors explain this phenomenon by the factthat these products, i.e. Tifluadom and U-50.488, have a specialaffinity for the opiate receptors of the kappa type and probably actlocally on these receptors situated in the gastric mucous membrane tobring about an increased discharge.

However, these compounds are mainly known to have a general analgesicactivity, of opiate type, when administered orally (Pharmaprojects - V &D Publications, Ltd - May and August 1988).

Reportedly, this activity does not bring about a dependence effect, likemorphine, but is accompanied by a tolerance phenomenon which requiresthe product to be administered in increasing quantities in order toachieve the desired effect.

So far these compounds have only been used as pharmacological reagentsand are not known to have been used in human therapy in the form ofdrugs.

The present invention has as its object a medicament acting on thegastrointestinal tract by both an antispasmodic effect and by the effectof increasing gastric discharge, these actions, however, having more orless no central effect and dependence or addiction phenomena.

The medicament is characterized in that it contains as active ingredientthe dextrorotatory enantiomer of an ether amino oxide: (+)1-[(3,4,5-trimethoxy)benzyloxymethyl]-1-phenyl-N,N-dimethyl-n-propylamineof formula ##STR2## and its pharmaceutically acceptable acid additionsalts.

The present invention was realized in an unforeseen manner by successivestudies, the essential feature of which is described as follows:

In U.S. Pat. No. 4,301,163 the applicant has claimed protection foraminoethers having local anaesthetic, spasmolytic and analgesicproperties.

In order to define more precisely this last property of the compoundmentioned in Example 2 of the patent, the optical resolution of thisracemic product was carried out to produce, on the one hand, thedextrorotatory enantiomer which is the product of this invention and, onthe other hand, the levorotatory enantiomer.

It is recognized that the "in vitro" study of the opiate receptorbinding affinity is a means of studying potentially analgesic compounds(Opiate receptor binding in Drug Research. Eric J. Simon in "Receptorbinding in Drug Research" p. 183-202 - Ed. Robert A. O'Brien-Dekker-1986).

The optically active compounds as well as those preferred in the U.S.Patent, the product called U 50.488 and morphine as reference productwere involved in this test according to the method described by F. Romanet al. in J. Pharm. Pharmacol. 1987, 39, p. 404-407.

At the end of the study it was found that the product of the inventiondistinguishes itself from the other compounds by the fact that it showsa receptor binding affinity to the receptors mu, delta and kappa studiedwhich is in contrast to the preferred compounds of the aforementionedU.S. Patent, which show above all a mu affinity, and to the compound U50.488 which, as reported, binds specifically to the kappa receptors.These results are indicative of the potential analgesic activities ofthese products (CRC Handbook of Stereoisomers: Drugs inPsychopharmacology CRC Press, Inc - 1984 p. 402); they were thusinvolved in an "in vivo" test considered to be suitable for determiningthis effect.

Surprisingly, the compound of the invention was virtually without anyanalgesic effect in this test, in contrast to other products which showthemselves to be active.

A last attempt to determine the expression "in vivo" of the propertiesfound "in vitro" in relation to the product has now been made using thetest carried out by M. Gue et al. (Reference already cited).

When tested, the product of the invention clearly shows an activitywhich encourages gastric discharge of solids in dogs. Moreover, theeffect observed is inhibited by compounds recognised to be opiateantagonistic.

Hence, in an unexpected and special manner, the compound of theinvention which shows an "in vitro" affinity with the opiate receptorsmu, delta and kappa does not have "in vivo", as one would expect it, acentral analgesic activity, but a local activity on the opiate receptorsof the gastric mucous membrane, thus bringing about increased dischargeof solids in dogs.

Moreover, it is also remarkable that the product possesses anantispasmodic activity as well.

Hence, in an aqueous solution, and at a 1.70×10⁻⁵ molar concentrationthe product inhibits 50% of the amplitude of spasms caused by bariumchloride on the duodenum of the rat. In this test which is carried out"in vitro", morphine is inactive at a concentration of more than 5 timesgreater than that of the product of the invention.

The double effect of the product demonstrated by the increased gastricdischarge of the solids and the disappearance of intestinal spasms isparticularly significant on account of the extent of the actions on thevarious stages of the gastrointestinal tract.

Numerous disorders of the tract may well be treatable. Among otherexamples, mention is made of gastrointestinal disorders caused bytreatment with medicaments over a long period, such as certain analgesicor neuroleptic medicaments.

Thus, the product of the invention is suitable for normalizing theactivity of the gastrointestinal tract in patients treated withanalgesic compounds of the morphine type which are known to slow downgastric discharge and cause spasms of certain intestinal muscles(Goodman and Gilman's "The Pharmacological Basis of Therapeutics" - 6thed. 1980 - p. 503 to 504).

The tests and results mentioned above and which are the basis of theinvention are described in more detail in the following.

The comparative tests which made it possible to determine the particularproperties of the products of the invention, more particularly of (+)1-[(3,4,5-trimethoxy)-benzyloxymethyl]-1-phenyl-N-N-dimethyl-n-propylamineD-(-)-tartrate, which is preferred, have been carried out with racemiccompounds of U.S. Pat. No. 4,301,163, namely(+/-)1-[(3,4-dimethoxy)benzyloxymethyl]-1-phenyl-N,N-dimethyl-n-propylamine,(+/-)1-benzyloxymethyl-1-phenyl-N,N-dimethyl-n-propylamine, (+/-)1-[3,4,5-trimethoxy)benzyloxymethyl]-1-phenyl-N-methyl-n-propylamine and(+/-)1-(p-chlorobenzyloxymethyl)-1-(p-methoxyphenyl)N,N-dimethyl-n-ethylaminewhich are respectively the products of Examples 1, 3, 12 and 13described and declared to be the preferred ones of this patent.

Moreover, also used as products of comparison were:

the levorotatary enantiomer of the compound of the invention, i.e. (-)1-[(3,4,5-trimethoxy)benzyloxymethyl]-1-phenyl-N,N-dimethyl-n-propylamine,the preparation of which is described in the experimental part of thetext,

trimebutine (DCI) which is (+/-)-2-dimethylamino-2-phenyl-n-butyl3,4,5-trimethoxybenzoate, the object of French Patent No. 2 369 M andwhich has a chemical structure similar to that of the racemic compoundwhich corresponds to the product of the invention.

The compound coded U 50.488 described above as being active in gastricdischarge, i.e.trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]phenylacetamidewhich is recognized to be a centrally acting analgesic and antiepileptic(Pharmaprojects - published August 1988).

Finally, in these tests morphine has been used as an analgesic referencesubstance.

The activity of the enantiomer has, therefore, been compared to that ofracemic compounds. However, it is known that in practical tests thereceptors involved are stereo-selective and that they are onlysusceptible to the activity of one single enantiomer, the other beinginactive, as has been described in the "CRC Handbook of Stereoisomers"Ed. Donald F. Smith. 1984, p. 401 to 440: "Opiates agonists andantagonists: Pharmacological behavorial, and neurochemical effects ofstereoisomers". In the tests carried out and with regard to thecomparisons this fact has been taken account of, and for a racemiccompound the number of the result of the test will be multiplied by twoand for a result of given value the dose of the racemic productresponsible for the effect will be divided by two, before comparing itwith the result of the compound of the invention.

As has already been mentioned, the binding affinity of the products tothe opiate receptors mu, delta and kappa was measured according to themethod described by F. Roman et al. (cited above).

The results are shown in the following Table 1 and are expressed in CI₅₀representing the nanomolar concentrations of the dissolved productcapable of inhibiting 50% of the binding of a specific radioactiveligand to the receptor studied.

                  TABLE 1                                                         ______________________________________                                        Binding affinity of the compound and of the                                   products of comparison to the receptors mu,                                   delta and kappa                                                                                 mu       delta    kappa                                     Test compound     receptor receptor receptor                                  ______________________________________                                        Product of the invention                                                      (+) Enantiomer    196        540      232                                     (-) Enantiomer    580      12 320   2 630                                     Ex. 1 of U.S. Pat. No. 4,301,163                                                                1 110    7 800    1 110                                     Ex. 3 of U.S. Pat. No. 4,301,163                                                                190      14 700     560                                     Ex. 12 of U.S. Pat. No. 4,301,163                                                               360      2 250    2 280                                     Ex. 13 of U.S. Pat. No. 4,301,163                                                               250      4 390      900                                     Trimebutine       146      1 750    1 460                                     U. 50.488         1 028    14 610     66                                      Morphine           7         152      127                                     ______________________________________                                    

When considering these results and even when making the correctionsuggested above to the racemic compounds, which has not been mentionedin Table 1, it is remarkable that the dextrorotatory enantiomer of theinvention is the only compound with morphine showing an affinity to thethree receptors studied, with a non-negligible intensity.

On the other hand, when looking only at the mu receptor, the compoundsof the Examples 3, 12 and 13 of the U.S. Patent as well as trimebutineare just as, if not more active. The same applies to the compound U.50.488 if one considers only the kappa receptor.

As the compound affinity to opiate receptors (in vitro) is oftenrepresentative of analgesic pharmacological properties (CRC Handbook ofStereoisomers - cited above), the products were involved in a test "invivo" suitable to demonstrate this analgesic activity in general.

This test carried out on mice according to a method derived from that ofKoster R. (Fed. Proc. 1959, 18, p.412) consists in studying theinfluence of products administered orally to the animal, on themanifestations of pain, caused by administering an acetic acid solutionintraperitoneally.

For this purpose, the animals in groups of 10 are given nothing to eator to drink for 20 hours before the test. However, they receive theproducts to be studied as an aqueous solution at the rate of 2 ml ofsolution per 100 g body weight, then 10 minutes later an intraperitonealinjection of 0.25 ml of an acetic acid solution at 0.5% (v/v) kept at37° C. Three minutes after this injection the number of abdominal crampsshown by the animals are counted for 10 minutes. The animals areconsidered to suffer less pain, if they show a number of cramps which isbelow half the average of the cramps shown by animals of the controlgroup. In the test the products have been administered in a dose of 50mg per kg, morphine used as reference and administered orally at a rateof 10 mg per kg showing an analgesic effect of 78%.

Table 2 shows the results of this study. They demonstrate and confirmthe characteristics of the product of the invention which shows verylittle analgesic effect compared to the other compounds studied. Thesefindings are all the more marked, if the suggested correction has beenapplied for these racemic compounds. In this case, the dextrorotatoryenantiomer of the invention (17.60%) is virtually 3 times less analgesicthan the trimebutine (24.3×2=48.6%) and 5 times less (44.0×2=88.0%) thanthe compound of Example 12 of the U.S. Patent.

                  TABLE 2                                                         ______________________________________                                        Analgesic activity "in vivo"                                                  (50 mg/kg - orally)                                                           Test Compound        % analgesia (p)                                          ______________________________________                                        Product of the invention                                                      (+) Enantiomer       17.6 (*)                                                 Ex. 3 of U.S. Pat. No. 4,301,163                                                                   27.6 (*)                                                 Ex. 12 of U.S. Pat. No. 4,301,163                                                                  44.0 (***)                                               Ex. 13 of U.S. Pat. No. 4,301,163                                                                  27.9 (***)                                               Trimebutine          24.3 (**)                                                U. 50.488            90.0 (***)                                               ______________________________________                                         (p) probability  Student's T test                                             (*) p < 0.05                                                                  (**) p < 0.01                                                                 (***) p < 0.001                                                          

The research on the local activity of the product of the invention onthe opiate receptors of the gastric mucous membrane has been carried outaccording to a method following that described by M. Gue et al. (alreadymentioned).

The authors study the action of opiate compounds of type mu and typekappa in dogs after oral administration. When weak doses are used, theydo not observe an effect for the mu agonist compounds, whereas the kappaagonist type of compounds (such as U. 50.488) further the gastricdischarge of the solid phase of the meal in dogs. This effect had, bythe way, been inhibited by the opiate antagonistic compounds naloxoneand MR 2266 which are known to be antagonistic to both the mu and kappareceptors (D. Romer et al., Life Sciences, 31, p. 1217-1220, 1982).

In this study, the authors put forward the proposition that the opiatecompounds of the kappa agonist type, such as trifluadom and U. 50.488,when administered orally, modify the gastric discharge by their localaction.

In an attempt to show such an action with the product of the invention,this has been used in this test, compared with its levorotary enantiomerand trimebutine which is known for its regulatory activity of thegastrointestinal functioning.

The principle of the test consists in measuring the gastric content ofthe animals one hour after eating a meal comprising 400 g of solidmatter with 21.7% dry matter composed of:

7.7% proteins,

4.5% lipids,

6.9% carbohydrates

2.6% mineral salts

and 20 g of sheeps liver containing radiolabelled cyanocobalamine. Themeal is consumed within about 5 minutes by the animals. After one hour,the gastric content is collected by means of a small tube placedapproximately 10 cm into the pyloris before the experiment.

The collected sample is weighed and homogenized. Its radioactivity ismeasured and the amount of the gastric discharge expressed in percentageis calculated according to the formula: ##EQU1## in which:

cpm1 represents the radioactivity per gram of the mixed, radiolabelledliver,

P1 is the weight of the radiolabelled liver, added to the meal,

cpm2 is the radioactivity per gram of collected sample after one hour,

p is the weight of this sample collected after one hour.

In practice, each test is carried out on three dogs and consists inadministering to them, 20 minutes before eating the meal describedabove, a capsule containing the test product at a dose of 0.25 ml per kganimal weight or a capsule placebo which serves to determine the controlphenomenon of the discharge on the animal. The 3 dogs receive eachtreatment twice in random order. Finally, in a last series of tests 3dogs receive an intravenous administration of a solution of MR 2266 ornaloxone at the rate of 0.1 mg per kg of weight. The meal is presentedand ingested 20 minutes after the capsule containing the test producthas been administered. The evacuation values of the solid phases aremeasured as described before and compared using the test of Mann andWhitney (U test). The difference in comparison with the control valuesis considered significant when p is<or =0.05.

The effect of the test products is objectivised by the percentagevariation calculated according to the relation: ##EQU2##

The results obtained for this study are shown in Table 3.

                  TABLE 3                                                         ______________________________________                                        Effect of the products on the gastric                                         evacuation of solids in dogs                                                  Test product (*) Variation in %                                               ______________________________________                                        Product of the invention                                                      (+) Enantiomer   +110%                                                        id. + naloxone    +5%                                                         id. + MR 2266    +14%                                                         enantiomer (-)   +26%                                                         Trimebutine       -4%                                                         ______________________________________                                         (*) With the exception of the trimebutine which was administered in a dos     of 5 mg/kg, the products were administered at the rate of 0.25 mg/kg          according to the protocol described above.                               

The action of the product of the invention is undeniable: its effectdoubles the gastric evacuation of the solids in dogs one hour afteradministration, whereas the effect of its levorotatory enantiomer isfour times less significant. Moreover, the action observed is inhibitedat the same time by naloxone, which is more particularly antagonistic tothe mu receptors, and MR 2266 which is antagonistic to the kappareceptors, which makes it possible to attribute the discharge effect toa general activity of the agonist type on the local opiate receptors ofthe gastric mucous and more particularly on the mu and kappa receptors.

The antispasmodic activity of the product of the invention in the formof its D (-)-tartrate has been researched "in vitro" on the duodenum ofthe rat which is an essential part of the intestinal tract of thisanimal.

The study consists in bringing about, on a fragment of this tissue,contractions caused by a spasmogen agent which is barium chloride inthis study, and then in calculating the concentration (IC₅₀) of thesolution of the product capable of inhibiting 50% of the amplitude ofthe contractions caused.

The results of the study are shown in Table 4

    ______________________________________                                        Antispasmodic activity "in vitro" on the                                      duodenum of rats                                                              (Spasmogen BaCl.sub.2)                                                        Test product      IC.sub.50  mol. liter                                       ______________________________________                                        Product of the invention                                                      (+) Enantiomer    1.70 · 10.sup.-5                                   Papaverine        2.74 · 10.sup.-5                                   Morphine          Inactive at 10.sup.-4                                       ______________________________________                                    

Although morphine is inactive in this test, the product of the inventionshows an activity slightly above that of papaverine which is consideredto be the reference compound for th spasmolytic activity.

Finally, the study of the acute toxicity of the product of the inventionis also significant in particular with regard to its levorotatoryenantiomer.

This toxicity has been studied orally in male mice. The test productshave been administered at the rate of 2 ml of their aqueous solution per100 g of animal weight. The animals are then observed for 3 hours afteradministration, then daily for fourteen days, when they are sacrificedand then an autopsy is carried out.

The LD₅₀ (lethal doses which cause the death of 50% of the animals) havebeen calculated according to the method of Reed J. L. and Muench H. (Am.J. Hyg. 1939, 27, p. 493). The results obtained are shown in thefollowing Table 5 and show that the product of the invention is abouthalf as toxic in this test than its levorotatory antipode.

                  TABLE 5                                                         ______________________________________                                        High toxicity, by oral method, in mice                                        Test product      LD.sub.50  mg/kg                                            ______________________________________                                        Product of the invention                                                      (+) Enantiomer    407                                                         (-) enantiomer    255                                                         ______________________________________                                    

The studies described above undoubtedly show the significance of theproduct of the invention, the particular properties of which consisting,on the one hand, in a local activity of agonist type on the opiatereceptors on the gastric mucous and, on the other hand, in anantispasmodic activity, in particular at the intestinal level, justifyits dual usefulness in treating digestive disorders, to which gastricmotility is linked, such as the gastro-oesophagian reflux, ulcers,dyspepsia, gastritis, functional colopathy and biliary dyskinesia.

As active ingredient of the medicament according to the invention thefree amine may be used which is(+)-1[(3,4,5-trimethoxy)-benzyloxymethyl]-1-phenyl-N,N-dimethyl-n-propylamine,or its addition salts with the pharmaceutically acceptable organic ormineral acids. As such hydrochloric, hydrobromic, phosphoric, sulphuricacids as well as acetic, citric, gluconic, maleic acids are used. As faras the organic acids are concerned, D-(-) tartaric acid gives thepreferred addition salt with the compound of the invention since, on theone hand, its purification by crystallization in ethanol is easy andefficient and, on the other hand, it is soluble in water and, therefore,suitable for the preparation of aqueous pharmaceutical forms withoutbeing hygroscopic. It has the physico-chemical stability necessary forits use as an agent in the pharmaceutical industry.

A further aspect of the invention is a process for preparing thedextrorotatory aminoether oxide and its D-(-) tartrate which may beobtained:

by the preferred process similar to that described in U.S. Pat. No.4,301,163 and which consists in reacting(+)-2-dimethylamino-2-phenyl-n-butanol prepared according to the methoddescribed in the Japanese patent application published under No.16416/1980 on 1st May 1980, with a 3,4,5-trimethoxybenzyl halide offormula ##STR3##

in which X is a halide atom which is chlorine, bromine or iodine.

This means more precisely that, firstly, a metallic alcoholate of thedextrorotatory aminoalcohol is prepared by reaction with an alkalimetal, such as sodium, potassium or their hydrides or amides. Thisreaction is generally carried out in aromatic solvents, such as benzene,toluene, xylene or in ethereal solvents, such as diethyl ether, dioxane,tetrahydrofuran or in solvents such as dimethylsulphoxide,dimethylformamide, acetonitrile, dimethylacetamide,hexamethylphosphoro-triamide. The salification reaction is effected byusing 0.7 to 1.5 moles of metallic reagent per mole of alcohol and,preferably, 0.9 to 1.2 moles of said reagent. The salificationtemperature is between 0° and 140° C., more particularly between 20° and110° C.

The metallic salt of the amino alcohol is formed after a reaction timeof 30 minutes to 6 hours, then it is condensed with the3,4,5-trimethoxybenzyl halide at a temperature of between 0° and 140°C., preferably 70° to 110° C. The condensation lasts between 1 to 24hours, preferably between 2 and 6 hours, and may be followed towards theend of the reaction by thin layer chromatography. The separation of theproduct formed is carried out by conventional methods described in theillustrating Example.

The dextrorotatory amino ether oxide obtained may be salified with thesuitable acids already mentioned. In a preferred manner, this operationmay be carried out by using D-(-) tartaric acid at the rate of 0.75 to1.25 mole per mole of the product to be salified. The reaction iscarried out in solvents, such as ketones or alcohols of low molecularweight. Ethanol is preferred, used at the rate of 3 to 10 volumes perpart by weight of isomer. Hence, for 1 mole, 5 to 7 volumes per weightof ethanol and 0.95 to 1.05 mole of D-(-) tartaric acid are usuallyadded. The reaction is carried out at a temperature of between 20° and80° C. lasting between 15 minutes to 5 hours, more particularly between30 minutes and 1 hour at a temperature between 35° and 50° C. Thecrystallization of the salt is completed after 48 hours at 20° C. afterwhich the D-(-) tartrate of the dextrorotatory isomer of the inventionmay be obtained by filtration in a state of purity which is satisfactoryfor its therapeutic use. However, if necessary, the product may bepurified by recrystallization in ethanol,

i.e. by resolution of the racemic amino ether oxide prepared as inExample 2 of U.S. Pat. No. 4,301,163.

In a conventional manner, this resolution is effected by separatingdiastereoisomers formed after salification with optically active acids.This process is commonly practiced. A particularly comprehensivecompilation of the reagents and their use can be found in "OpticalResolution Procedures for Chemical compounds"--Vol. 1: Amines andrelated compounds. Paul Newman--1978.

In more precise terms the process consists in salifying thecorresponding racemic propylamine, dissolved in a solvent which may be aketone or an alcohol with a boiling point below or near 80° C., by usinga (+) dextrorotatory organic acid to yield an insoluble(+)-acid/(-)-propylamine salt; in removing this insoluble salt byfiltration in order to obtain a solution containing both (+) acid andthe (+) enantiomer of the n-propylamine; in evaporating the solvent ofthis solution to dryness in order to obtain a residue, in dissolving theresidue in water and in alkalising the solution up to a pH near or above10 by adding an alkali metal or alkaline earth or ammonium hydroxidesolution, in extracting the free dextrorotatory n-propylamine with anorganic solvent, and then in evaporating the extracted organic solventin order to obtain the desired (+)-n-propylamine.

When carrying out this method of resolution, tartaric acid enantiomersare preferred. When using these, diastereoisomers are formed in a firstphase with L-(+)-tartaric acid, the diastereoisomer formed between theacid and the levorotatory enantiomer which crystallises is then removedby filtration, the filtrate is then treated to free its salt and toseparate the dextrorotatory isomer of n-propylamine which is the objectof the invention and finally, the addition salt is prepared withD-(-)-tartaric acid, the salt which may finally be purified as describedabove.

In order to effect the resolution of one mole of racemic compound, 0.6to 1.5 moles of L-(+)-tartaric acid are used to salify the amine in asolvent which, preferably, is an alcohol or a ketone of low molecularweight and a boiling point near or below 80° C. This solvent shouldpreferably be anhydrous. Absolute ethanol is most frequently used at therate of 3 to 30 parts by volume per part by weight of compound to betreated.

Salification is carried out by heating the solution obtained for 5minutes to 1 hour under reflux of the solvent, then by cooling to allowthe diastereoisomer formed from L-(+)-tartaric acid and the levorotatoryenantiomer of the compound of the invention to crystallise.

This salt which is a by-product is removed by filtration. The filtrateis then treated in a suitable manner in order to obtain thedextrorotatory enantiomer of the invention. To this end, the solvent isremoved by distillation, the residue is taken up in an alkaline solutionin a sufficient quantity in order to obtain a pH near or above 10, theproduct of the invention is then extracted in a suitable solvent, suchas ether or methylene chloride.

After evaporating this extracted solvent, the dextrorotatory enantiomerof the invention is purified as described above by forming an additionsalt, particularly with D-(-)-tartaric acid which is preferred, thenpurified by crystallising this salt.

These processes are illustrated in a non-restrictive manner in theexperimental part by way of examples which describe the process andcharacteristics of the products of the invention obtained.

The usefulness of the product of the invention and its salts has beenshown in the treatment of various disorders of digestive motility.According to the nature and seriousness of the disorder to be treatedthe daily therapeutic dose should contain between 5 and 1000 mg,preferably between 25 and 500 mg of the product, which may be taken onceor several times.

The product is presented in conventional pharmaceutical form, such astablets, capsules, suppositories, solutions or suspensions which aresuitable for drinking, spraying or injecting.

For the galenic or so-called "dry" forms the quantity active ingredientmay be 5 to 80% by weight of the finished product, the total of theexcipients may be at the rate of 95 to 20% of said weight. In theso-called "aqueous" forms (suspensions and solutions) the activeingredient may be 0.1 to 20% by weight of the composition, water andvarious additives representing 99.9 to 80% of the total weight of thefinished preparation.

The preparations of injectable solutions at 0.5% (w/v) and thepreparation of coated tablets of a dose of 100 mg (-)-tartrate of thecompound of the invention per unit are shown by way of illustration

Formulations *Injectable solution, 0.5% (w/v)

Compounds for the preparation of 100 ml of solution:

    ______________________________________                                        (-)-tartrate of (+)-1-[(3,4,5-trimethoxy)benzyloxy-                                                      0.500 g                                            methyl]-1-phenyl-N,N-dimethyl-n-propylamine                                   sodium chloride for injections                                                                           0.850 g                                            distilled water for injectable preparations                                                              100.0 ml                                           q.s.p                                                                         ______________________________________                                    

Preparation

The compounds are dissolved in approximately 95% of the quantity ofdistilled water prescribed for the preparation, at a temperature around20° C., while stirring. The solution obtained is filtered through amembrane of a porosity of 22 microns, then the filtrate made up to theexact volume with distilled water which has also been filtered. Thesolution is packaged at a rate of 5 ml per ampoule, the ampoules arethen sealed and sterilised at 121° C. for 30 minutes.

*Coated tablets with 100 mg of agent per unit

Formula per unit

    ______________________________________                                        (-)-tartrate of (+)-1-[(3,4,5-trimethoxy)benzyloxy-                                                      100.0  mg                                          methyl]-1-phenyl-N,N-dimethyl-n-propylamine                                   dicalcium phosphate        30.0   mg                                          lactose                    132.0  mg                                          maize starch               80.0   mg                                          carboxymethyl cellulose    10.0   mg                                          polyvinylpyrrolidone 25    16.0   mg                                          microcrystalline cellulose 20.0   mg                                          magnesium stearate         4.0    mg                                          talcum                     8.0    mg                                          hydroxypropylmethyl cellulose                                                                            4.4    mg                                          titanium dioxide           1.1    mg                                          for a total of             405.5  mg                                          ______________________________________                                    

Preparation

The following is introduced into a mixer-kneader:

    ______________________________________                                        active ingredient       1750 g                                                dicalcium phosphate      525 g                                                lactose                 2320 g                                                maize starch            1400 g                                                carboxymethyl cellulose  175 g                                                ______________________________________                                    

for moistening a solution of 1.05 g of polyvinylpyrrolidone 25 in 770 mlof purified water is added to the mixture obtained. The mixture isgranulated in an apparatus fitted with a 2 mm mesh, the grains areoven-dried at 50° C., then calibrated by passing them through a 1 mmmesh.

346 g of microcrystalline cellulose, 69 g of magnesium stearate and 139g of talcum are added to 6365 g of these granules in a mixer. Aftermixing, the product is compressed to 401.5 mg per unit, the tabletsobtained are coated in a centrifuge at 40° C. using an aqueoussuspension of titanium dioxide and hydroxypropylmethyl cellulose inorder finally to obtain the finished coated tablets at an average weightof 406.7 mg of unit weight and each containing 100 mg of (-)-tartrate ofthe product of the invention.

EXPERIMENTAL PART Preparation processes *Example 1 (preferred) a)(+)-1-[(3,4,5-trimethoxy)benzyloxymethyl]-1-phenyl-N,N-dimethyl-n-propylamine

Into a reactor, protected from humidity and under nitrogen atmosphere,are introduced 60 ml of anhydrous dioxan, then 6.20 g of sodium hydridein an 80% by weight suspension (w/w) in paraffin (0.207 mol).

While stirring and without exceeding 50° C., 40 g (0.207 mol) of(+)-2-dimethylamino-2-phenyl-butanol ([α]_(D) =+7.9°; C=1, ethanol) areintroduced. The suspension is stirred at 40° C. for a further 45minutes, then cooled down to a temperature near 20° C.

Within 2 hours and without exceeding 50° C., 44.9 g (0.207 mol) of3,4,5-trimethoxybenzyl chloride in 5 ml of anhydrous dioxan areintroduced. The reaction medium is heated to 70°-75° C. and kept up atthis temperature for 5 hours. After cooling down, the mixture is leftovernight, then 200 ml of water are added slowly, while maintaining atemperature below 20° C. After acidification to pH 1 by sulphuric acid,it is extracted with 60 ml of toluene.

The toluene phase is isolated and removed. The acid phase is alkalizedwith a concentrated sodium hydroxide solution, then extracted twice with150 ml of methylene chloride.

The combined organic phases are washed in water, then dried with Na₂SO₄. The solvent is distilled. The product obtained is in the form of apale yellow, viscous oil.

Weight: 70.30 g.

Yield: 91%.

1H - NMR - CDCl₃ (60 MHz, TMS int) - chemical shifts in ppm: 0.70(triplet, 3H), 1.95 (quadruplet, 2H); 2.32 (singlet, 6H) 3.90 (singlet,11H), 4.55 (singlet, 2H); 6.65 (singlet, 2H) 7.35 (broad, 5H).

[α]_(D) =+16.5°(c=6, ethanol).

b) Salification by D-(-)-tartaric acid

3.50 g (9.38 mmol) of the dextrorotatory enantiomer prepared as above,1.37 g (9.13 mmol) of D-(-)-tartaric acid and 21 ml of absolute ethanolare introduced into a reactor.

While stirring, the mixture is heated to 50° C. and kept at thistemperature for 30 minutes. The solution is gradually cooled down toapproximately 10° C. within 16 hours. The crystals are filtered anddried in vacuo at 50° C. until they reach a constant weight.

Weight: 4.06 g.

Yield=85%.

mp=147° C.

[α]_(D) ²⁵ =+14.5° (c=5, HCl N).

A sample of this product is recrystallised in boiling ethanol (5 volumesper part by weight). The crystals obtained have a melting point and anoptical rotation which are identical to the product before treatment. Inconclusion, the values of the melting point and the optical rotationmentioned above are considered to be characteristic of the purifiedproduct.

*Example 2 a) Resolution of the racemic compound

Into a reactor, protected from humidity, 210 ml of absolute ethanol, 30g (80.3 mmol) of(+/-)-1-[(3,4,5-trimethoxy)benzyloxymethyl]-1-phenyl-N,N-dimethyl-n-propylamineare introduced. Then 9.6 g (64.2 mmol) of L-(+)-tartaric acid are addedand, while stirring, the mixture is heated under reflux which is kept upfor 15 minutes.

The solution obtained is gradually cooled down to 20° C., whilestirring, then left for one night.

The undissolved part is filtered and removed. It contains essentiallythe L-(+)-tartrate of the levorotatory enantiomer of the product of theinvention which is purified in order to obtain a sample for comparison,by recrystallizing it in absolute ethanol at the rate of 5 volumes perparts by weight of product until it reaches a constant optical rotation:

[α]_(D) =-14.5° (c=5, HCl N).

The alcoholic filtrate of the first crystallisation containing theproduct of the invention is evaporated in vacuo and the residuedissolved in 160 ml of water.

The solution is alkalized to pH 10 with a concentrated sodium hydroxidesolution, then extracted twice with 120 ml of methylene chloride. Thecombined organic phases are washed in water, then dried with Na₂ SO₄.After removal of the methylene chloride by distillation, a pale yellow,oily residue enriched in dextrorotatory isomer is obtained.

Weight: 16.50 g.

Yield by weight: 55%.

[α]=+14.7° (c=6, ethanol) - optical purity=89%.

b) Salification by D-(-)-tartaric acid

The method described in b) of Example 1 is then followed, using 12.6 g(33.7 mmol) of the former product and 5.05 g (33.7 mmol) ofD-(-)-tartaric acid in 110 ml of anhydrous ethanol. The crystallizedproduct is filtered and dried.

Weight: 13.8 g.

Yield by weight: 78%.

mp=143°-145° C. [α]_(D) ²⁵ =+13.8° (c=5, HCl N).

optical purity=95%.

The product is recrystallized in 65 ml of ethanol under reflux. Afterhaving been cooled down slowly to 20° C., while stirring, the crystalsare filtered and dried in vacuo until they reach a constant weight.

Weight: 12.4 g.

Yield by weight: 90%.

mp=147° C. [α]_(D) ²⁵ =+13.8° (c=5, HCl N).

A sample product is treated in an alkali medium and extracted withmethylene chloride. The pale yellow, oily residue obtained afterevaporation has an optical rotation [α]_(D) of +16.6° at a concentrationof 6% (w/v) in ethanol. When calculated, this value is considered to becharacteristic of the optical purity of the dextrorotatory isomer whichis the object of the invention.

We claim:
 1. A method of stimulating gastric emptying in an animal in the essential absence of any analgesic effect which comprises administering to an animal an effective dosage of crystallized (+)-1-[(3,4,5-trimethoxy)-benzyloxymethyl]-1-phenyl-N,N-dimethyl-N-propylamine having the formula ##STR4## or its pharmaceutically acceptable acid addition salt.
 2. The method of claim 1 wherein the salt is (+)-1-[(3,4,5-trimethoxy)-benzyloxymethyl]-1-phenyl-N,N-dimethyl-N-propylamine D-(-)-tartrate.
 3. A process for normalizing the gastrointestinal tract of a patient treated with an analgesic compound comprising administering to said patient in an amount effective to normalize the gastrointestinal tract crystallized (+)-1-[(3,4,5-trimethoxy)-benzyloxymethyl]-1-phenyl-N,N-dimethyl-N-propylamine having the formula ##STR5## or its pharmaceutically acceptable acid addition salt.
 4. A method for increasing gastric discharge in a subject which comprises administering to the subject a medicament consisting essentially of the (+) enantiomer of 1-[(3,4,5-trimethoxy)-benzyloxymethyl]-1-phenyl-N,N-dimethyl-n-propylamine or a pharmaceutically acceptable acid addition salt thereof in a crystallized form and in an amount which is therapeutically effective to increase the gastric discharge of solids from the subject and to provide antispasmodic activity while substantially avoiding the generation of analgesic activity.
 5. The method of claim 4 which further comprises forming the acid addition salt by reaction with an optically active enantiomer of an organic acid.
 6. The method of claim 4 which further comprises forming the acid addition salt by reaction with D(-)tartaric acid.
 7. The method of claim 4 which further comprises preparing the (+) enantiomer by forming a metallic alcoholate of (+)-2-dimethylamino-2-phenyl-n-butanol and condensing the alcoholate with a 3,4,5-trimethoxy benzyl halide.
 8. The method of claim 4 which further comprises preparing the (+) enantiomer by forming diastereomers of racemic 1-[(3,4,5-trimethoxy-benzyloxymethyl]-1-phenyl-N,N-dimethyl-n-propylamine with a (+) enantiomer of an organic acid, removing the (-) enantiomer of the amine by crystallization and separation from the remaining filtrate and treating the filtrate to obtain the (+) enantiomer of the amine.
 9. The method of claim 4 which further comprises preparing the (+) enantiomer by forming diastereomers of racemic 1-(3,4,5-trimethoxy)-benzyloxymethyl]-1-phenyl-N,N-dimethyl-n-propylamine with a L-(+)-tartaric acid, removing the (-) enantiomer of the amine by crystallization and subsequent separation from the remaining filtrate and treating the filtrate to obtain the (+) enantiomer of the amine.
 10. The method of one of claims 7, 8 or 9 which further comprises forming the acid addition salt by reaction with D(-)tartaric acid to purify the (+) enantiomer salt of the amine.
 11. The method of claim 4 which further comprises administering the medicament at a daily therapeutic dose of between about 5 and 1000 mg of the (+) enantiomer.
 12. The method of claim 4 which further comprises preparing the medicament in the form of a tablet, capsule, suppository, solution or suspension.
 13. The method of claim 12 wherein the (+) enantiomer constitutes at least about 5 to 80% by weight of the medicament.
 14. The method of claim 12 wherein the medicament is in the form of an aqueous solution or suspension with the (+) enantiomer constitutes at least about 0.1 to 20% by weight thereof.
 15. The method of claim 4 wherein the gastric discharge is increased by at least about 4 times as much as the corresponding (-) enantiomer of the amine and wherein the D₅₀ toxicity of the (+) enantiomer is less than one-half that of the corresponding (-) enantiomer of the amine.
 16. A method for normalizing the activity of the gastrointestinal tract of a subject who has been treated with analgesic compounds, which comprises administering to the subject a medicament consisting essentially of the (+) enantiomer of 1-[(3,4,5-trimethoxy)-benzyloxymethyl]-1-phenyl-N,N-dimethyl-n-propylamine or a pharmaceutically acceptable acid addition salt thereof in a crystallized form and in an amount which is therapeutically effective to increase the gastric discharge of solids from the subject and to provide antispasmodic activity so that the effects of the analgesic compounds are reduced and the gastrointestinal tract activity is substantially returned to normal.
 17. The method of claim 16 which further comprises forming the acid addition salt by reaction with an optically active enantiomer of an organic acid.
 18. The method of claim 16 which further comprises forming the acid addition salt by reaction with D(-)tartaric acid.
 19. The method of claim 16 which further comprises preparing the (+) enantiomer by forming a metallic alcoholate of (+)-2-dimethylamine-2-phenyl-n-butanol and condensing the alcoholate with a 3,4,5-trimethoxy benzyl halide.
 20. The method of claim 16 which further comprises preparing the (+) enantiomer by forming diastereomers of racemic 1-[(3,4,5-trimethoxy)-benzyloxymethyl]-1-phenyl-N,N-dimethyl-n-propylamine with a (+) enantiomer of an organic acid, removing the (-) enantiomer of the amine by crystallization and separation from the remaining filtrate and treating the filtrate to obtain the (+) enantiomer of the amine.
 21. The method of claim 16 which further comprises preparing the (+) enantiomer by forming diastereomers of racemic 1-[(3,4,5-trimethoxy)-benzyloxymethyl]-1-phenyl-N,N-dimethyl-n-propylamine with a L-(+)-tartaric acid, removing the (-) enantiomer of the amine by crystallization and subsequent separation from the remaining filtrate and treating the filtrate to obtain the (+) enantiomer of the amine.
 22. The method of one of claims 19, 20 or 21 which further comprises forming the acid addition salt by reaction with D(-)tartaric acid to purify the (+) enantiomer salt of the amine.
 23. The method of claim 16 which further comprises administering the medicament at a daily therapeutic dose of between about 5 and 1000 mg of the (+) enantiomer.
 24. The method of claim 23 which further comprises preparing the medicament in the form of a tablet, capsule, suppository, solution or suspension.
 25. The method of claim 24 wherein the (+) enantiomer constitutes at least about 5 to 80% by weight of the medicament.
 26. The method of claim 24 wherein the medicament is in the form of an aqueous solution or suspension with the (+) enantiomer constitutes at least about 0.1 to 20% by weight thereof.
 27. The method of claim 16 wherein the gastric discharge is increased by at least about 4 times as much as the corresponding (-) enantiomer of the amine and wherein the D₅₀ toxicity of the (+) enantiomer is less than one-half that of the corresponding (-) enantiomer of the amine. 